1. Field of the Invention
This invention relates to nitrogen mustard derivatives which possess good antitumor activity against leukemia and other tumors and particularly to nitrogen mustards derived from carbohydrates.
2. Description of the Prior Art
Nitrogen mustards were among the first chemotherapeutic agents rationally applied to the treatment of tumors. In many ways, modern cancer chemotherapy can be said to have begun with the discovery of the clinical activity of certain nitrogen mustards against lymphoid neoplasms during studies made on the biological effects and therapeutic applications of certain chemical warfare agents during World War II. However, the high chemical reactivity of nitrogen mustards and the high probability of nonselective reaction with diverse nucleophilic centers available in vivo result in numerous toxic side effects. In particular, damage to bone marrow and other rapidly dividing normal cells limits the use of basic nitrogen mustards (such as nitrogen mustard itself: 2-chloro-N-(2-chloroethyl)-N-methylethaneamine) limits the usefulness of these compounds. In fact, the damaging effects of nitrogen mustards on bone marrow provided the initial clue which first suggested that the mustards might also affect the growth of lymphoid tumors.
Nitrogen mustard (mechlorethamine) represents the standard for comparison in the mustard class of alkylating agents. It has substantial therapeutic activity for a number of human tumors, including Hodgkin's and non-Hodgkin's lymphomas. It is actively used in the treatment of Hodgkin's disease, as a component of the MOPP regimen (Devita et al, Annals Internal Med. 73, 891-895, 1970). Approximately 70-80% of patients are cured on this regimen. However, the substantial acute and chronic bone marrow toxic properties of nitrogen mustard serve as a severe limiting factor in its clinical use, as discussed above for the class in general. Many patients, at least 20%, require a substantial reduction in dose (perhaps to sub-therapeutic levels) because of extreme depression of white blood cell count. With repeated courses of treatment, there is a threat of cumulative injury with a resultant state of chronic bone marrow hypoplasia. L-PAM (L-phenylalanine mustard) has similar limitations because of severe bone marrow toxicity. In contrast to nitrogen mustard, the nadir of white blood cell count is somewhat delayed with L-PAM, and the injury to the bone marrow is more cumulative.
Numerous derivatives of nitrogen mustard have been synthesized in an effort to reduce toxic effects while retaining the desired chemotherapeutic activity. See, for example, Burger's Medicinal Chemistry 4th Ed., Part II, M. E. Wolff, Ed., John Wiley & Sons, New York, (1979), pages 619-633 for a review of chemotherapeutic alkylating agents, most of which are derivatives of or have structural features in common with nitrogen mustard.
A few amino glucose mustards have been developed in the more recent past and tested for antitumor activity against P388 leukemia and L1210 leukemia (Wampler et al, Can. Res. 35, 1903-1906 (1975)). These compounds employed a glucose moiety carrying a nitrogen mustard at position C-2. Reist et al, J. Amer. Chem. Soc. 82, 2025-2029 (1960) discusses the synthesis of a C-6 glucose mustard without mentioning its possible biological activity. Other sugar mustards showing good activity include 1,6-di-(2-chloroethyl)amino-1,6-dideoxy-D-mannitol dihydrochloride, developed by Vargha et al, J. Chem. Soc., 1957, 810-812.
However, none of these studies have indicated any suppression of damage to bone marrow. Accordingly, there remains a need for therapeutically active compounds which retain their activity against rapidly dividing tumor cells but which have reduced activity against bone marrow.